Many of us find ourselves swimming along in the tranquil sea of life when suddenly a crisis hits — a death in the family, the loss of a job, a bad breakup. Some power through and find calm waters again, while others drown in depression.

Scientists continue to search for the underlying genes and neurobiology that dictate our reactions to stress. Now, a study using mice has found a switch-like mechanism between resilience and defeat in an area of the brain that plays an important role in regulating emotions and has been linked with mood and anxiety disorders.

After artificially enhancing the activity of neurons in that part of the brain — the medial prefrontal cortex — mice that previously fought to avoid electric shocks started to act helpless. Rather than leaping for an open escape route, they sat in a corner taking the pain — presumably out of a belief that nothing they could do would change their circumstances.

“This helpless behavior is quite similar to what clinicians see in depressed individuals — an inability to take action to avoid or correct a difficult situation,” said study author and neuroscientist Bo Li of the Cold Spring Harbor Laboratory in New York. The results were published online May 27 in the Journal of Neuroscience.

Because there is no true animal equivalent to the depression that affects humans, researchers instead model certain symptoms of the disorder, such as despair and, in this case, helplessness.

Researchers at Cold Spring Harbor Laboratory identify the neurons in the brain that determine if a mouse will learn to cope with stress or become depressed. These neurons, located in a region of the brain known as the medial prefrontal cortex (top, green image) become hyperactive in depressed mice. The bottom panel is close-up of above image - yellow indicates activation. The team showed that this enhanced activity causes depression. (Bo Li /Cold Spring Harbor Laboratory)

In his famous 1967 experiment on dogs, American psychologist Martin Seligman discovered that helplessness can be learned. He put a dog into a box with two chambers divided by a barrier that could be jumped over. When one chamber became electrified, the dog ran around frantically, finally scrambling over the barrier to escape the shock. In later trials, evading the shock becomes easier and easier for the animal until it would just stand next to the barrier waiting to jump.

But the outcome is much more grim if a dog first learns that electric shocks are uncontrollable and unavoidable. If animals are repeatedly shocked while tied up beforehand, then later placed in the same box free to roam, most didn’t jump the barrier. Instead, they lay down while whining and taking the jolt. Subsequent trials showcased the animal’s same passive, defeatist response.

Seligman formed a theory he called learned helplessness. It occurs when an animal or human has learned that outcomes are uncontrollable and thus fails to take any action in the future despite a clear ability to change its situation.

Learned helplessness has been observed in human experiments, such as subjects enduring a loud, disturbing noise if they had been taught that it wasn’t under their control. Since then, the theory has been used to build up the human spirit. (Seligman set up a resilience-training program for U.S. Army soldiers to do this.) Before President Obama banned the practice, the CIA used sleep deprivation, stress positions and sometimes multiple methods while interrogating detainees in order to create a “state of learned helplessness and dependence” in them.

In Li’s experiment, mice were put into a two-chambered cage with a door between them that at first was closed. For one hour, they were subjected to inescapable foot shocks in an unpredictable manner, giving them the impression that nothing could be done to prepare for or avoid the jolts. This learning period occurred over two days. On the third day, the door opened to allow the mice to escape by running into the other chamber that was not electrified.

After a few trials, most mice avoided the shocks by standing near the door, waiting for it to open and running through to the other chamber. But about 20 percent developed learned helplessness.

“They sit in the corner and just take the shock,” said study author and biologist Zina Perova, who worked on the study in Li’s group as a graduate student. “It’s this belief of ‘No matter what I do, it won’t change anything’ — it’s hopelessness.”

The team investigated which part of the brain lit up during such an experiment by using a genetically modified mouse whose neurons glow green when activated.

After the learned-helplessness trials, the researchers extracted brain slices and found that neurons were tagged with green in the medial prefrontal cortex.

Then they looked closely at these tagged neurons, searching for differences among the two groups of mice. Li and his colleagues discovered that the neurons from helpless mice had more nodes of connection and mice that showed determination had fewer. They presumed that this could mean an increase and decrease, respectively, in how active those neurons were.

To verify that, the researchers artificially boosted activity in the medial prefrontal cortex of resilient mice — those that easily escaped the shocks. The mice suddenly became helpless. A switch seemed to flip in their brains, and the previously strong rodents lost their determination and failed to avoid the painful jolts. Although learned helplessness can be overcome through antidepressant drugs or if an experimenter shows the animal how to escape, the researchers had never seen once-persevering mice turn helpless before.

Next, Li hopes to investigate whether the switch goes the opposite way — whether inhibition of activity of these neurons makes helpless mice strong — and suspects that it may.

If so, the results would be consistent with deep brain stimulation, a treatment for depression that uses electrical impulses to inhibit neuronal activity in a targeted brain area.

The study “tells us pretty clearly that the medial prefrontal cortex is important in anxiety and stress behaviors,” said neuroscientist Amit Etkin of Stanford University, who was not involved in the study. “There’s a lot of interest in doing deep brain stimulation in that area.”

In addition to emotion regulation, the medial prefrontal cortex has been implicated in such tasks as decision-making and memory retrieval.

“It’s thought to be an area important for understanding your environment and how you fit in,” said neurobiologist Ronald Duman of Yale University, who also was not involved in the research. “So disruption of that may alter how you feel about yourself in that environment.”

Duman notes that other areas of the brain have been associated with depression in prior studies as well, such as the hippocampus and amygdala. Our complex brain circuitry — how all these parts interact — likely complicates any easy translation of this switch mechanism to humans.

“To really understand what’s going on, we have to get down to the level of how [the medial prefrontal cortex] is talking to other brain regions,” Etkin said.

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